•Fig. 14.10 Principalmechanismsdeterminingmyoplasmic[Ca++]insmoothmuscle.Releaseofcalciumfromthesarcoplasmicreticulum(SR)isarapidinitialeventinactivation,whereasboththeSRandthesarcolemmaparticipateinthesubsequentstimulus-dependentregulationofmyoplasmic[Ca++].Thesarcolemmaintegratesmanysimultaneousexcitatoryandinhibitoryinputstogovernthecellularresponse.Higher-orderregulatorymechanismscanaltertheactivityofvariouspumps,exchangers,orenzymes(theasterisk designateswell-establishedinstances).ThelabelATP indicatesthattheprocessrequiresATPhydrolysis;thequestion mark onthesarcolemmareferstotheCa++ pathwayimportantforrefillingtheSR(i.e.,store-operatedCa++ entry[SOCE]),whichappearstoinvolvetheinteractionofaCa++-sensitivestromalinteractionmolecule(STIM)ontheSRandthesarcolemmalCa++ channelOrai.CaCM,Ca++-calmodulincomplex;G,guaninenucleotide–bindingproteins;IP3,inositol1,4,5-trisphosphate;MLCK,myosinlight-chainkinase;PIP2,phosphatidylinositolbisphosphate;PLC,phospholipaseC.
Inappropriatecontractionofsmoothmuscleisassociatedwithmanypathologicalsituations.Oneexampleissustainedvasospasmofacerebralarterythatdevelopsseveralhoursafterasubarachnoidhemorrhage.Itisthoughtthatfreeradicalsgeneratedasaresultofthehemorrhageraisemyoplasmic[Ca++]insurroundingarterialsmoothmusclecells.Theriseinmyoplasmic[Ca++]activatesMLCK,whichleadstocross-bridgephosphorylationandcontraction.Thevasoconstrictiondeprivesotherareasofthebrainofoxygenandmayleadtopermanentinjuryordeathofsurroundingneurons.Forafewdaysthecerebralarteryremainssensitivetovasoactiveagents,andthereforetreatmentwithvasodilatorsmayrestoreflow.AnincreaseinROKactivityandMPphosphorylationhasbeenobservedduringcerebralvasospasm.AdministrationofROKinhibitorspromotesrelaxationofthevasospasmanddecreasesthelevelofmyosinlight-chainphosphorylation.Thesmoothmusclecellsceasetorespondtothevasodilatorsafterseveraldays,andtheylosecontractileproteinsandsecreteextracellularcollagen.Thelumenofthearteryremainsconstrictedasaresultofstructuralandmechanicalchangesthatdonotinvolveactivecontraction.
[Ca++] of smooth muscle. This differs from skeletal muscle, in which action potential–induced release of Ca++ from the SR fully activates the contractile apparatus.